Cyclooxygenase-2 (COX-2) has been implicated as a rate-limiting step in the development of colon cancer. This enzyme is the committed step in the synthesis of prostaglandins, which are derived from the fatty acid, arachidonic acid. The bases for focusing on the COX-2 isoform of cyclooxygenase is that COX-2 is overexpressed in both adenomas and carcinomas, inhibitors of COX-2 block the progression to colon cancer, and genetic experiments demonstrate that its deletion in a mouse model of colon cancer is strongly protective. A number of subsequent responses have been described but it still is not clear which of these are causally responsible for maintaining the pathway to cancer. Studies have implicated the availability of fatty acids that serve as substrates for COX-2 as having a role in colon carcinogenesis. Substrate abundance is regulated by multiple factors, including concentration in the diet and relevant enzymatic pathways. An additional and potentially important factor in colon cancer is that excessive signaling via the epidermal growth factor receptor (EGFR) pathway has been observed in cancer cells. Carcinomas show increased activity of this pathway and multiple experiments suggest that it plays an important role in pathogenesis.